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Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad

An intermediate and representative technology, applied in the field of preparation of gout treatment drug Lesinurad, can solve the problems of complicated operation, expensive raw materials and high cost, and achieve the effects of simple operation, easy separation and purification, and low price

Active Publication Date: 2014-01-22
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This step is complicated to operate and the raw materials are expensive, which is not conducive to cost reduction
In addition, most of the existing Lesinurad preparation methods use thiophosgene, which is inconvenient to operate and not safe. Although the Chinese patent CN102040546A adopts the method of avoiding the use of thiophosgene, this method greatly prolongs the synthesis route of Lesinurad, making the process more complex and costly

Method used

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  • Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad
  • Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad
  • Preparation method of gout curative medicine Lesinurad and midbody of Lesinurad

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1 prepares compound 12 by compound 1

[0063]

[0064] In a single-necked bottle, add 4-cyclopropyl-1-naphthylamine (compound 1, 1.0eq), add DMF (8.2Vol) to dissolve it, add NaOH (1.2eq) and CS 2 (1.2eq), stirred and reacted at room temperature for 1h, added hydrazine hydrate (3.0eq) and transferred to 70°C oil bath, stirred and refluxed for 4h, LC confirmed that the reaction was complete, stopped heating and stirring, added 10mL water per 1g of raw material after cooling, and suction filtered , the filter cake was recrystallized with 95% ethanol, suction filtered, and the solid was dried to obtain compound 12 with a yield of 50%-70%.

[0065] The NMR data of the product are as follows: 1 H NMR (400MHz,DMSO)δ9.16(s,1H),8.43(d,J=7.8Hz,1H),7.98–7.89(m,1H),7.66-7.48(m,3H),7.26(d, J=7.6Hz,1H),5.54–4.50(m,1H),2.46–2.34(m,1H),1.12–1.02(m,2H),0.80–0.69(m,2H).

Embodiment 2

[0066] Embodiment 2 prepares compound 13 by compound 12

[0067]

[0068] Add compound 12 (1.0eq) in the single-necked bottle, add 1,4-dioxane (7.5Vol) to make it dissolve, add N,N-dimethylformamide dimethyl acetal (1.0eq), at 100 Stir and reflux at ℃ for 1.5-2h, LC confirmed the completion of the reaction, after cooling the reaction solution to room temperature, add 10mL of water to 1g of the raw material, the precipitated solid was suction filtered, the filter cake was washed twice with 95% ethanol, and the solid was dried to obtain compound 13【Lesinurad Intermediate, chemical name: 4-(4-cyclopropylnaphthalene)-3-mercapto-1,2,4-triazole)]. The yield is 70%-80%.

[0069] The NMR data of the product are as follows: 1 H NMR(400MHz,DMSO)δ8.69(s,1H),8.57(d,J=8.4Hz,1H),7.72(t,J=7.3Hz,1H),7.64(t,J=7.4Hz,1H ),7.54(d,J=7.6Hz,1H),7.44–7.37(m,2H),2.56–2.50(m,1H),1.19-1.09(m,2H),0.90–0.75(m,2H).

Embodiment 3

[0070] Embodiment 3 prepares compound 15 by compound 13

[0071]

[0072] The NMR data of the product are as follows: Compound 13 (4g, 1eq) was added to a single-necked bottle, and the solvent DMF (67mL, 16.8vol) was added to dissolve, stirred at room temperature, and K 2 CO 3 (2.272g, 1.1eq), then add compound 14 (1.74mL, 1.05eq) dropwise, control the drop rate at 0.5mL / min, stir at room temperature for 2h, the reaction is complete, add EA (ethyl acetate) and water to dilute the reaction solution, extracted three times with EA, washed three times with saturated brine, anhydrous MgSO 4 dry. The organic phase was spin-dried to obtain a white solid [that is, compound 15, a Lesinurad intermediate, chemical name: 4-(4-cyclopropylnaphthalene)-3-ethyl thioacetate-1,2,4-triazole], After drying, 5.13 g was obtained, and the yield was 97%.

[0073] The NMR data of the product are as follows: 1 H NMR (400MHz, CDCl 3 )δ8.54(d,J=8.4Hz,1H),8.30(s,1H),7.70-7.62(m,1H),7.61-7.53(m,...

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Abstract

The invention provides a novel Lesinurad midbody and provides a synthesis process of Lesinurad, which is economic, efficient, safe, environment-friendly and applicable to large-scale industrial production. The invention further provides a method for preparing the conventional Lesinurad midbody and Lesinurad by using the novel Lesinurad midbody. When synthesized from the novel Lesinurad midbody provided by the invention, the Lesinurad has advantages that the price of necessary raw materials is low, the raw materials are easy to obtain, heavy metal and solvents which are harmful to the environment are not used, the midbody and a product can be easily separated and purified, the operation is easy, application of thiophosgene which is high in toxicity and not easy to operate is avoided, and the total reaction yield is approximate to or higher than that in the prior art.

Description

technical field [0001] The invention relates to a preparation method of Lesinurad, a drug for treating gout, and a key intermediate thereof. Background technique [0002] Gout is a crystal-associated arthropathy caused by deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by disturbance of purine metabolism and / or decreased uric acid excretion. There are more than 20 million gout patients worldwide. Lesinurad (RDEA594) is an oral uricosuric agent that inhibits the renal proximal tubule uric acid transporter URAT1. Previous exploratory studies in gout patients have shown that allopurinol (ALLO), combined with lesinurad, can reduce serum uric acid (SUA) more effectively than ALLO alone. Through the study of more than 500 healthy people and gout patients, it was found that Lesinurad reduced blood uric acid in a dose-dependent manner, and Febuxostat was well tolerated. It is also a xanthine oxidase inhibitor approved for the treatment of h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12C07C335/40
CPCC07C335/40C07D249/12
Inventor 王鹏李丕旭谷向永
Owner SUZHOU PENGXU PHARM TECH CO LTD
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